Sexually transmitted diseases (STDs) affect 340 million new people per year, with herpes simplex virus type 2 (HSV-2) infection impacting a startling ~17 percent of U.S. adults and 536 million people worldwide. Development of better treatments is an urgent need, particularly due to its disproportional effect on women, newborns and immune-compromised individuals. In addition, it is now clear that HSV-2 infection increases the likelihood of human immunodeficiency (HIV) coinfection 6-fold and increases HIV, Chlamydia, and syphilis prevalence in third-world countries. Therefore better strategies to treat or prevent HSV-2 are expected to help decrease STD spread. Current options for prevention and treatment of HSV-2 include antivirals and topically applied microbicides. However, primarily due to difficulties in delivery and a lack of understanding of the immune response, antiviral strategies and vaccine development have proven only moderately successful, despite the identification of antigen-based targets. However, if applied to microbicide design, the multi-therapeutic targeting methodology typical of vaccines may enable increased efficacy. To aid in viral inhibition, mechanisms such as RNA interference (RNAi) - using targeted short interfering RNA (siRNA) molecules - can down-regulate specific proteins such as UL29.2 (a DNA binding protein affecting virus replication) and nectin-1 (a host cell receptor protein integral to initial viral binding and subsequent spread). In parallel, research at the protein level has uncovered monoclonal antibodies (mAbs) that can intercept virus attachment to host receptors such as nectin-1. Additionally, there are many new molecules available to enhance drug delivery and tissue penetration, including cell penetrating peptides, endosomal escape peptides, and stealth ligands that act through a variety of mechanisms. This project will test the hypotheses that administration of a polymeric PLGA nanoparticle-based microbicide, that incorporates: (1) siRNA to provide RNAi, (2) surface functionalization that modulates cell-virus interactions by enhancing NP uptake, (3) stealth properties for mucosal penetration, and (4) controlled release to enable prolonged therapeutic effect of the encapsulated agents, has the potential to increase viral inhibition both in vitro and in vivo. I expect this approach will improve current HSV-2 therapy and can be extended to multiple STD combinations, including elusive viruses such as HIV. PUBLIC HEALTH RELEVANCE: Sexually transmitted diseases (STDs) pose a significant global health threat, and herpes simplex virus type 2 (HSV-2) is particularly pervasive;its prominent role in STD coinfection, healthcare costs, societal ramifications, the impact on newborns and immune-compromised individuals, and recurrent infections, all contribute to the urgency to develop an efficacious treatment strategy. The short-term significance of this project is to develop a nanoparticle delivery system encapsulating short interfering RNA (siRNA) molecules, with surface functionalization, that interferes with HSV-2 infection by targeting the virus and host simultaneously, through multiple mechanisms (interfering with binding, uptake, and replication). This multimodal approach will improve current HSV-2 therapy and can be extended to multiple STD combinations, including elusive viruses such as HIV.